comorbidities – Prof G's MS Blog Archive

#ClinicSpeak: a double-whammy

If you thought having MS was bad enough the Swedish study below confirms that people with MS are more likely to have a raft of other diseases, which include cardiovascular disease (CVD), stroke, heart failure, venous thromboembolism, other autoimmune conditions, bowel dysfunction, depression and fractures. These results replicate what we see from other studies and are not dissimilar what we see in other autoimmune diseases such as rheumatoid arthritis (RA).

It is clear that some comorbidities, in particular, venous thromboembolism, bowel problems, depression and fractures, are probably due to MS. However, the other comorbidities are associated with MS. Why pwMS are at increased risk of CVD, stroke and heart failure is interesting and needs more study. Is it because pwMS live an unhealthy lifestyle; poor diet, less exercise and a higher rate of smoking? Or is the systemic inflammation that occurs in MS driving the vascular disease? Should we be doing trials to test preventive strategies to address this problem? I suspect the answer to all of these questions is YES.

#ClinicSpeak

What are the clinical implications of these findings? We know from other studies that pwMS with vascular and other comorbidities become disabled more quickly. A person with MS with vascular comorbidity will on average need a walking stick 6 years earlier than a pwMS who does not have vascular comorbidity. This 6-year gap is larger than the treatment effect of our platform therapies. Six years is a long time in the life of someone with MS.

Therefore, if you want to manage MS holistically pwMS need to be screened for comorbidities and have them managed. This is part of my marginal gains strategy. Who should do the comorbidity screening? In the UK it usually falls to the family doctor or GP to do this screening, but I have found many pwMS simply don’t see their GP regularly enough for health checks. This is why it may be important for you as individuals with MS, and a stake in your own health, to take control and have yourself screened.

More importantly, prevention is better than cure. So if you have MS you should do everything you can to prevent yourself from developing comorbidity. This means adopting a heart- and brain-healthy lifestyle; stop smoking, improving your diet, maintaining a healthy weight, exercising regularly, reducing your alcohol consumption to safe limits, having your blood pressure, cholesterol and sugar levels checked. In addition, you need the inflammation due to your MS controlled; this may require DMTs and a highly-effective DMT.

I am aware this advice is easier said than done, but at the end of the day, there is only so much that your HCP can do and a lot of the advice above is about self-management and empowering yourself to take responsibility for your own health.

Castelo-Branco et al. Non-infectious comorbidity in patients with multiple sclerosis: A national cohort study in Sweden. Mult Scler J Exp Transl Clin. 2020 Aug 14;6(3):2055217320947761.

Background: Comorbidity is of significant concern in multiple sclerosis (MS). Few population-based studies have reported conditions occurring in MS after diagnosis, especially in contemporary cohorts.

Objective: To explore incident comorbidity, mortality and hospitalizations in MS, stratified by age and sex.

Methods: In a Swedish population-based cohort study 6602 incident MS patients (aged ≥18 years) and 61,828 matched MS-free individuals were identified between 1 January 2008 and 31 December 2016, using national registers. Incidence rates (IRs) and incidence rate ratios (IRRs) with 95% CI were calculated for each outcome.

Results: IRs of cardiovascular disease (CVD) were higher among MS patients than MS-free individuals, (major adverse CVD: IRR 1.42; 95% CI 1.12-1.82; hemorrhagic/ischemic stroke: 1.46; 1.05-2.02; transient ischemic attack: 1.65; 1.09-2.50; heart failure: 1.55; 1.15-2.10); venous thromboembolism: 1.42; 1.14-1.77). MS patients also had higher risks of several non-CVDs such as autoimmune conditions (IRR 3.83; 3.01-4.87), bowel dysfunction (2.16; 1.86-2.50), depression (2.38; 2.11-2.68), and fractures (1.32; 1.19-1.47), as well as being hospitalized and to suffer from CVD-related deaths ((1.91; 1.00-3.65), particularly in females (3.57; 1.58-8.06)).

Conclusion: MS-patients experience a notable comorbidity burden which emphasizes the need for integrated disease management in order to improve patient care and long-term outcomes of MS.

CoI: multiple

#T4TD vascular comorbidities

Did you know if you have MS and vascular comorbidity you are likely to need a walking stick approximately 6 years earlier than if you did not have vascular comorbidity? Importantly this 6-year difference in reaching EDSS 6.0 (requiring a walking stick) is larger than the treatment effect of a platform DMT.

As vascular comorbidities are largely preventable are you doing anything to prevent or optimally treat your own comorbidities? If not, you need to ask yourself why not? Self-management and taking responsibility for your own health is the order of the day; this has become the new normal.

Vascular comorbidities = diabetes, hypertension, heart disease, hypercholesterolemia, peripheral vascular disease and smoking.

#T4TD = Thought for the Day

CoI: none for this post

How healthy is your lifestyle?

Barts-MS rose-tinted-odometer ★★★★★

It is a no-brainer. A healthy lifestyle is one of the most effective preventive health interventions available. The study below shows that you can increase your chances, by a factor of over 20, of a life expectancy free of diabetes, cardiovascular diseases, and cancer at age 50 by making ensuring you maintain 4 or 5 low-risk lifestyle factors; i.e. not smoking, staying trim, doing moderate to vigorous physical activity, keeping your alcohol intake moderate and eating a quality diet.

Although this study has implications for the general population the message is applicable to pwMS. All these lifestyle factors have been linked in some studies to MS outcomes. In other words, everyone with MS should assess their lifestyle to see if they can change things to maximise their longterm outcome.

Another thing you can do is to ask your HCP to score themselves on these five factors. I maintain that HCPs have a responsibility to lead by example and they should be practising what they preach. This is why I am determined this year to max-out on all five of these factors so that I can look my patients in the eye and say “I am with you all the way”.

What is not discussed in this paper is the fact that what determines your ability to live a ‘healthy life’ is often down to the social determinants of health (SDoH) and these are usually beyond the control of the individual. Education, poverty, inequality, social isolation, a poor environment, lack of self-control, a sense of helplessness, chronic stress, etc. are all factors that make adopting a healthy lifestyle almost impossible. This is why our #ThinkSocial campaign is really a political campaign. Without politicians acknowledging the importance of the SDoH little will change.

Please let us know if you are managing to adopt and maintain a healthy lifestyle and how you have done it; success stories are more motivating than pontificating from a soap-box.

Li et al. Healthy lifestyle and life expectancy free of cancer, cardiovascular disease, and type 2 diabetes: prospective cohort study. BMJ 2020;368:l6669

Objective: To examine how a healthy lifestyle is related to life expectancy that is free from major chronic diseases.

Design: Prospective cohort study.

Setting and participants: The Nurses’ Health Study (1980-2014; n=73 196) and the Health Professionals Follow-Up Study (1986-2014; n=38 366).

Main exposures: Five low-risk lifestyle factors: never smoking, body mass index 18.5-24.9, moderate to vigorous physical activity (≥30 minutes/day), moderate alcohol intake (women: 5-15 g/day; men 5-30 g/day), and a higher diet quality score (upper 40%).

Main outcome: Life expectancy free of diabetes, cardiovascular diseases, and cancer.

Results: The life expectancy free of diabetes, cardiovascular diseases, and cancer at age 50 was 23.7 years (95% confidence interval 22.6 to 24.7) for women who adopted no low-risk lifestyle factors, in contrast to 34.4 years (33.1 to 35.5) for women who adopted four or five low-risk factors. At age 50, the life expectancy free of any of these chronic diseases was 23.5 (22.3 to 24.7) years among men who adopted no low-risk lifestyle factors and 31.1 (29.5 to 32.5) years in men who adopted four or five low-risk lifestyle factors. For current male smokers who smoked heavily (≥15 cigarettes/day) or obese men and women (body mass index ≥30), their disease-free life expectancies accounted for the lowest proportion (≤75%) of total life expectancy at age 50.

Conclusion: Adherence to a healthy lifestyle at mid-life is associated with a longer life expectancy free of major chronic diseases.

CoI: multiple

Do you have high blood pressure?

Barts-MS rose-tinted-odometer ★ ★ ★ ★ ★

Who knows their current blood pressure?

If you have MS you should know your blood pressure, your BMI (body mass index), your lipid status and whether or not you have impaired glucose tolerance or diabetes. In other words, all pwMS should have an annual health check outside of their MS clinic appointment to be screened for comorbidities. We know that pwMS have a higher chance of developing comorbidities that speed up worsening disability. This is why the holistic management of MS is so important. Preventing the development of comorbidities is part of our treatment strategy to maximise the lifelong brain health of someone with MS. Even if we can’t prevent you developing a comorbid disease then aggressively managing comorbidities will help improve MS outcomes.

The substudy of the SPRINT hypertension trial (see below) shows that targeting a systolic BP of less than 120 mm Hg, compared with less than 140 mm Hg, was associated with a smaller increase in cerebral white matter lesion volume. This raises the question that if you have MS and are hypertensive should you be lowering your systolic blood pressure to less than 120 mm Hg or less than 140 mm Hg? I would suggest the former. Preventing new hypertension-related white matter lesions must be part of the treatment target for people with MS. It also makes it easier to interpret the annual monitoring MRI; we don’t want to escalate your DMT based on new vascular lesions.

Please note that pwMS who have one of four comorbidities (smoking, hypertension, diabetes or dyslipidaemia) do much worse than pwMS with no comorbidities. On average, pwMS with comorbidities need to use a walking stick 6 years earlier than pwMS who don’t have comorbidities. This 6-year difference in disability outcomes is bigger than the treatment effect of interferon-beta.

If you don’t know what your blood pressure it please make a point to see your family doctor or pharmacist or you can purchase or borrow a self-administered BP machine to check your own BP on a regular basis. This should be part of your MS self-management.

SPRINT MIND Investigators for the SPRINT Research Group. Association of Intensive vs Standard Blood Pressure Control With Cerebral White Matter Lesions. JAMA. 2019 Aug 13;322(6):524-534. doi: 10.1001/jama.2019.10551.

IMPORTANCE: The effect of intensive blood pressure lowering on brain health remains uncertain.

OBJECTIVE: To evaluate the association of intensive blood pressure treatment with cerebral white matter lesion and brain volumes.

DESIGN, SETTING, AND PARTICIPANTS: A substudy of a multicenter randomized clinical trial of hypertensive adults 50 years or older without a history of diabetes or stroke at 27 sites in the United States. Randomization began on November 8, 2010. The overall trial was stopped early because of benefit for its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. Brain magnetic resonance imaging (MRI) was performed on a subset of participants at baseline (n = 670) and at 4 years of follow-up (n = 449); final follow-up date was July 1, 2016.

INTERVENTIONS: Participants were randomized to a systolic blood pressure (SBP) goal of either less than 120 mm Hg (intensive treatment, n = 355) or less than 140 mm Hg (standard treatment, n = 315).

MAIN OUTCOMES AND MEASURES: The primary outcome was change in total white matter lesion volume from baseline. Change in total brain volume was a secondary outcome.

RESULTS: Among 670 recruited patients who had baseline MRI (mean age, 67.3 [SD, 8.2] years; 40.4% women), 449 (67.0%) completed the follow-up MRI at a median of 3.97 years after randomization, after a median intervention period of 3.40 years. In the intensive treatment group, based on a robust linear mixed model, mean white matter lesion volume increased from 4.57 to 5.49 cm3 (difference, 0.92 cm3 [95% CI, 0.69 to 1.14]) vs an increase from 4.40 to 5.85 cm3 (difference, 1.45 cm3 [95% CI, 1.21 to 1.70]) in the standard treatment group (between-group difference in change, -0.54 cm3 [95% CI, -0.87 to -0.20]). Mean total brain volume decreased from 1134.5 to 1104.0 cm3 (difference, -30.6 cm3 [95% CI, -32.3 to -28.8]) in the intensive treatment group vs a decrease from 1134.0 to 1107.1 cm3 (difference, -26.9 cm3 [95% CI, 24.8 to 28.8]) in the standard treatment group (between-group difference in change, -3.7 cm3 [95% CI, -6.3 to -1.1]).

CONCLUSIONS AND RELEVANCE: Among hypertensive adults, targeting an SBP of less than 120 mm Hg, compared with less than 140 mm Hg, was significantly associated with a smaller increase in cerebral white matter lesion volume and a greater decrease in total brain volume, although the differences were small.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01206062.

CoI: multiple

What’s your excuse?

What will it take to get me to stop smoking?

If you are a smoker and continue to smoke you need to think about how you want to manage your own MS. We debate endlessly about the lack of progress in developing effective treatments to slow down the worsening of MS and ignore the obvious. The first study below implies that by simply stopping smoking it will have a major impact on the outcome of your MS. Do you want to stop smoking? If you do please ask your GP or family doctor to refer you to a stop smoking cessation clinic; please note it is very difficult to stop smoking without professional help.

I am going to use this post to blow our own trumpet. In this week’s New England Journal of Medicine is a paper from a group in our University showing that e-cigarettes are superior to nicotine replacement therapies in getting people to stop smoking. This is good news; e-cigarettes give those who are really addicted to nicotine the necessary ‘nicotine hit’, whilst reducing the harm associated with cigarettes. In my opinion, there is now really now no excuse for someone with MS to continue smoking. Or am I wrong?

How smoking speeds up the onset and rate of progressive MS is unknown. Smoking may simply unregulate proinflammatory mechanisms, reduce recovery mechanisms in the brain and spinal cord or speed up the development of comorbidities in particular vascular disease, which in turn speeds up the rate of worsening in progressive MS.

The effect of smoking on progressive MS may be independent of it being a risk factor for developing MS in the first place. We need more research in this area to see what it is about smoking that triggers MS. Based on other Swedish data it appears that it is something that is in smoked tobacco that is to blame. In Sweden use of snuff or non-smoked tobacco, does not increase your risk of getting MS; in fact, the risk of getting MS in snuff users is actually lower than that of the general population.

With my #PreventMS hat on is that if we get the population not to start smoking in the first place we can prevent 1 in 5 future people from developing MS. This is why it upsets me so much when my own children smoke. Even more worrying is that if you are loaded with the correct genetic factors that predispose you to develop MS your odds of getting MS are increased dramatically if you smoke. The latter is more reason to make sure your brothers and sisters, children, nephews and nieces don’t smoke. Tragically this is easier said than done.

Study 1

Ramanujam et al. Effect of Smoking Cessation on Multiple Sclerosis Prognosis. JAMA Neurol. 2015 Oct 1;72(10):1117-1123.

IMPORTANCE: Smoking tobacco is a well-established risk factor for multiple sclerosis (MS), a chronic inflammatory disorder of the central nervous system usually characterized by bouts and remissions and typically followed by a secondary progressive (SP) course. However, it is not clear whether smoking after diagnosis is detrimental.

OBJECTIVE: To determine whether smoking after MS diagnosis is associated with a change in time to SP disease.

DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of patients with prevalent MS who smoked at diagnosis (n = 728) taken from the Genes and Environment in Multiple Sclerosis Study, which consists of patients from the Swedish National MS Registry. The study entrance date was at time of first-year smoking. The study was conducted between November 2008 and December 2011, with patient environmental data collected from November 2009 to March 2011 via questionnaire. Study participants were from all counties in Sweden diagnosed as having MS at the time of the Genes and Environment in Multiple Sclerosis Study and registered in the Swedish National MS Registry. Patients with MS with relapsing-remitting disease course or SP were included. These patients’ conditions were diagnosed according to the McDonald criteria and the patients responded to recruitment letters with detailed questionnaires.

EXPOSURE: Smoking, considered yearly after diagnosis and combined into a time-invariant covariate before diagnosis.

MAIN OUTCOMES AND MEASURES: Time to SPMS, measured using an accelerated failure time model, with smoking as a time-varying covariate. Other covariates included sex, age at diagnosis, snuff use, and smoking before diagnosis.

RESULTS: The optimized model illustrated that each additional year of smoking after diagnosis accelerated the time to conversion to SPMS by 4.7% (acceleration factor, 1.047; 95% CI, 1.023-1.072; P < .001). Kaplan-Meier plots demonstrated that those who continued to smoke continuously each year after diagnosis converted to SPMS faster than those who quit smoking, reaching SP disease at 48 and 56 years of age, respectively.

CONCLUSIONS AND RELEVANCE: This study provides evidence that continued smoking is associated with an acceleration in time to SPMS and that those who quit fare better. Therefore, we propose that patients with MS should be advised to stop smoking once a diagnosis has been made, not only to lessen risks for comorbidities, but also to avoid aggravating MS-related disability.

Study 2

Hajeck et al. A Randomized Trial of E-Cigarettes versus Nicotine-Replacement Therapy. N Engl J Med. 2019 Jan 30.

BACKGROUND: E-cigarettes are commonly used in attempts to stop smoking, but evidence is limited regarding their effectiveness as compared with that of nicotine products approved as smoking-cessation treatments.

METHODS: We randomly assigned adults attending U.K. National Health Service stop-smoking services to either nicotine-replacement products of their choice, including product combinations, provided for up to 3 months, or an e-cigarette starter pack (a second-generation refillable e-cigarette with one bottle of nicotine e-liquid [18 mg per milliliter]), with a recommendation to purchase further e-liquids of the flavor and strength of their choice. Treatment included weekly behavioral support for at least 4 weeks. The primary outcome was sustained abstinence for 1 year, which was validated biochemically at the final visit. Participants who were lost to follow-up or did not provide biochemical validation were considered to not be abstinent. Secondary outcomes included participant-reported treatment usage and respiratory symptoms.

RESULTS: A total of 886 participants underwent randomization. The 1-year abstinence rate was 18.0% in the e-cigarette group, as compared with 9.9% in the nicotine-replacement group (relative risk, 1.83; 95% confidence interval [CI], 1.30 to 2.58; P<0.001). Among participants with 1-year abstinence, those in the e-cigarette group were more likely than those in the nicotine-replacement group to use their assigned product at 52 weeks (80% [63 of 79 participants] vs. 9% [4 of 44 participants]). Overall, throat or mouth irritation was reported more frequently in the e-cigarette group (65.3%, vs. 51.2% in the nicotine-replacement group) and nausea more frequently in the nicotine-replacement group (37.9%, vs. 31.3% in the e-cigarette group). The e-cigarette group reported greater declines in the incidence of cough and phlegm production from baseline to 52 weeks than did the nicotine-replacement group (relative risk for cough, 0.8; 95% CI, 0.6 to 0.9; relative risk for phlegm, 0.7; 95% CI, 0.6 to 0.9). There were no significant between-group differences in the incidence of wheezing or shortness of breath.

CONCLUSIONS: E-cigarettes were more effective for smoking cessation than nicotine-replacement therapy, when both products were accompanied by behavioral support. (Funded by the National Institute for Health Research and Cancer Research UK; Current Controlled Trials number, ISRCTN60477608 .).

Study 3

Hedström et al. Smoking is a major preventable risk factor for multiple sclerosis.Mult Scler. 2015 Oct 12. pii: 1352458515609794.

BACKGROUND: Both smoking and exposure to passive smoking have repeatedly been associated with increased multiple sclerosis (MS) risk, but have never before been studied together. We assessed the public health impact of these factors.

METHODS: In a Swedish population-based case-control study (2455 cases, 5336 controls), we calculated odds ratios of developing MS associated with different categories of tobacco smoke exposure, together with 95% confidence intervals, by using logistic regression. The excess proportion of cases attributable to smoking and passive smoking was calculated as a percentage.

RESULTS: Both smoking and exposure to passive smoking contribute to MS risk in a dose-dependent manner. At the population level, 20.4% of all cases were attributable to smoke exposure. Among subjects carrying the genetic risk factor HLA-DRB1*15 but lacking HLA-A*02, 41% of the MS cases were attributable to smoking.

CONCLUSIONS: From a public health perspective, the impact of smoking and passive smoking on MS risk is considerable. Preventive measures in order to reduce tobacco smoke exposure are, therefore, essential. In particular, individuals with a history of MS in the family should be informed regarding the impact of smoking on the risk of MS, and the importance of preventing their children from being exposed to passive smoke.

What is end-organ damage?

Help! How do I manage progressive brain atrophy in a patient who is NEDA-3?

End-organ damage is a catch-all phrase for the degeneration of the brain; it occurs as part of the ageing process that some consider pathological and others as a normal fact of life. I have hinted that I consider it both because end-organ damage is potentially modifiable via lifestyle modifications and pharmacological interventions. If it was a normal process it should not be modifiable. How can you be more normal than normal? Making ageing a disease also has political ramifications, for example, it will almost certainly incentivise Pharma to develop treatments for ageing.

In MS end-organ damage is massively accelerated by the MS disease process itself, i.e. inflammation and demyelination, and from delayed downstream processes triggered by inflammation, for example, energy failure, microglial activation, ongoing inflammation driven by antibodies, possible slow viral infection and its consequences and comorbidities. It is clear that all people with MS will have end-organ damage, but what can we do about it? To be honest, apart from early treatment to prevent damage, we haven’t got an evidence base about how to manage this problem in MS.

As an example, I saw a patient earlier this week. He has relapsing-remitting MS diagnosed in the mid-2000s and started on interferon-beta (Avonex). He also has type 1 diabetes which he developed when he was 14 years of age, 8 years before he was diagnosed with MS. His diabetes was poorly controlled initially but is now well controlled on an insulin pump. He has renal (proteinuria), eye (retinopathy) and hypertension as complications of his diabetes. His hypertension is controlled on medication. He has been relapse-free and his MRI has not shown any obvious new lesions over the last 6 years; i.e. he is NEDA-3. He does not smoke, but he drinks between 3 and 4 units of alcohol per day. He was referred to me because he is sick and tired of injecting himself with interferon and he has heard of a new drug called ocrelizumab. He wants to be switched to it because is more efficacious and only give every 6 months. His treating neurologist said no, hence his referral to me for a second opinion.

When I went through his history it is clear he has had no relapses in the last 6 years and is fully functional and working full-time. I reviewed his MRIs and I agree he has no new lesions over the last 6 years, but he has developed quite profound and progressive brain atrophy over this timeframe; he is definitely not NEDA-4. What do I do?

Do I switch him from interferon-beta to ocrelizumab? Or do I leave him on Avonex, which is doing its job and rendering him NEDA-3?

If I do switch him to ocrelizumab, will it normalise his brain volume loss? Will he become NEDA-4?

What is causing his brain volume loss? MS, hypertension, diabetes, alcohol or something else?

Do I tell him about his gross brain atrophy, which he is blissfully unaware of?

Do I offer him a formal cognitive assessment to see if he has cognitive impairments? If he has a cognitive assessment and they come back abnormal, which they are likely to, how do I tell him? Will knowing he cognitively impaired affect his management?

Do I offer him a lumbar puncture to measure his spinal fluid neurofilament levels?

Do I recommend any add-on off-label treatments that may help?

Or do I just take the easy option and send him back to his neurologist with a recommendation to leave things as is?

Can I suggest we debate these issues over the next few days and I can then potentially do a live webinar on the issue of end-organ damage and how to handle the problem of progressive brain volume loss on DMTs when you are NEDA-3.